Automated installation procedure for a disposable flow path

ABSTRACT

This invention provides an automated installation procedure for assembling a disposable flow path: providing a disposable flow path comprising tubing and a plurality of sensors onto a re-usable instrument; qualifying said tubing and said plurality of sensors to be on the flow path based on a standard; and determining if the tubing and the plurality of sensors comply with characteristics and performance according to limits for specifications or acceptance criteria.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a filing under 35 U.S.C. §371 and claims priority tointernational patent application No. PCT/SE2009/050664 filed Jun. 4,2009, published on Dec. 30, 2009 as WO 2009/157852, which claimspriority to U.S. provisional patent application No. 61/075,456 filed onJun. 25, 2008.

FIELD OF THE INVENTION

The present invention relates to an automated installation procedure fora disposable flow path.

BACKGROUND OF THE INVENTION

Generally, chromatography is the collective term for a family oftechniques that may be used in a laboratory in order to separatemixtures. This laboratory technique usually involves sending a mixturedissolved in a “mobile phase” through a stationary phase, where thisstationary phase separates the analyte to be measured from othermolecules in the mixture and allows it to be isolated.

There are several types of chromatography, such as gas or liquidchromatography. Gas chromatography is a separation technique in whichthe mobile phase is a gas. Gas chromatography is always carried out in acolumn, which is typically in a packed mode or capillary mode. Liquidchromatography is a separation technique in which the mobile phase is aliquid. The liquid chromatography can be carried out either in a columnor a plane. Present day liquid chromatography generally utilizes verysmall packing particles and a relatively high pressure is referred to ashigh performance liquid chromatography

ÄKTAREADY™ is a liquid chromatography system using disposable flowpaths, i.e. ÄKTAREADY™ flow paths, manufactured by GE Healthcare inUppsala, Sweden. The ÄKTAREADY™ system is based on proven liquidchromatography techniques, such as ion exchange, affinitychromatography, and hydrophobic interaction. This ÄKTAREADY™ systemincludes a disposable flow path system with UNICORN™ software thatenables it to perform automated liquid chromatography. The system ischaracterized by a re-usable instrument that is equipped with a clean,preferably pre-sterilized, flow path prior to operation. By exchangingthe flow path in between chromatographic runs and processes, the needfor cleaning, cleaning validation and the risk for cross-contaminationis eliminated. The flow path comprises all wetted parts in fluid contactduring operation, including tubing, sensor components, fluid treatmentcomponents (e.g. air trap) and connectors.

However, there are problems with using the disposable flow path systemin the ÄKTAREADY™ system, because the manual interaction of the userwith the system during replacement of the disposable flow path may leadto improper installation (or removal) of components of the flow pathsystem. For example, the availability of different tubing sizes of theflow path components may lead to malfunction of the system if wrongparts are installed by the user and there is no procedure for automaticrecognition of the flow path components in place that may prevent theuser from using a wrongly installed system. Also, if the components arenot installed properly then the analyte may not be properly measuredfrom other molecules and it may not be isolated. Additionally, there isa problem of qualifying newly installed flow path components accordingto their specification limits, i.e. the sensor components, prior to thechromatographic run in a safe and failure proof manner.

Further, there is another problem with the disposable flow path in thata “traditional” Installation Qualification and Operation Qualificationwould “contaminate” the flow kit and it would not be “clean” enough tobe used for purification without doing a cleaning in place procedure.With the ÄKTAREADY™ system the Installation and Operation Qualificationare completed by utilizing the complementary flow kit to qualify theperformance of the cabinet only.

Therefore, there is a need for a system and method that enables the userto install components of the flow path system and qualify thefunctionality of the system components in order for the analyte (orproduct) to be properly measured from other molecules in the mixture andto allows the analyte (or product) to be isolated as intended.

SUMMARY OF THE INVENTION

The present invention has been accomplished in view of theabove-mentioned technical background, and it is an objective of thepresent invention to provide an automated installation procedure for adisposable flow path of a chromatography column.

In a preferred embodiment of the invention, an automated installationprocedure for assembling a flow path is disclosed. The procedureincludes: providing a disposable flow path including tubing and aplurality of sensors onto a re-usable instrument; qualifying said tubingand said plurality of sensors to be on the disposable flow path based ona standard; and determining if the tubing and the plurality of sensorscomply with characteristics and performance according to limits forspecifications or acceptance criteria.

In another preferred embodiment of the invention, a computer implementedmethod for assembling a disposable flow path is disclosed. The methodincludes: providing a disposable flow path comprising tubing and aplurality of sensors onto a re-usable instrument; qualifying said tubingand said plurality of sensors to be on the disposable flow path based ona standard; and determining if the tubing and the plurality of sensorscomply with characteristics and performance according to limits forspecifications or acceptance criteria.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of a typical ÄKTAREADY™ system in accordance withan embodiment of the invention.

FIG. 2 is a schematic of a disposable flow path used on the re-usableÄKTAREADY™ instrument of FIG. 1 in accordance with the invention.

FIG. 3 is a schematic of the flow scheme the ÄKTAREADY™ system of FIG. 2in accordance with invention.

FIG. 4 is a flow-chart that depicts an automated installation procedurefor assembling a disposable flow path in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

The presently preferred embodiments of the invention are described withreference to the drawings, where like components are identified with thesame numerals. The descriptions of the preferred embodiments areexemplary and are not intended to limit the scope of the invention.

FIG. 1 illustrates a schematic of the typical ÄKTAREADY™ system. TheÄKTAREADY™ system is an isocratic, low pressure, automated liquidchromatography system that utilizes disposable ÄKTAREADY™ flow paths.The ÄKTAREADY™ system is based on proven liquid chromatographytechniques, such as ion exchange, affinity chromatography andhydrophobic interaction. The ÄKTAREADY™ system is biocompatible andhygienic, and meets all and cGMP (current Good manufacturing practice)demands for Phase I-III in drug development and final-scale production.This ÄKTAREADY™ system 100 includes: an ÄKTAREADY™ cabinet unit 101, anÄKTAREADY™ flow path 103, a Ready to Process column 105, a columntrolley 107 and UNICORN™ software (not shown).

FIG. 2 is a schematic of a flow-kit of the ÄKTAREADY™ system. Flow path103 also referred to as flow path 200 includes: an inlet manifold 201, apump tubing 203, a flow cell for pressure sensor 205, an air trap 207,an air vent tubing 209, a column inlet connection 211, a column outletconnection 213, a flow cell for pressure sensor 215, a pH electrode 217,a flow meter cell 219, a temperature cell 221, a conductivity sensor223, an ultraviolet flow cell 225, a flow cell for pressure sensor 227and an outlet manifold 229. Inlet manifold 201 has 6 inletscorresponding to sanitary connectors (TC), which are connected to thepump tubing 203. Pump tubing 203 is a double pump tubing used formounting a peristaltic pump. Also, pump tubing 203 increases efficiencyand reduces pulsation.

Pump tubing 203 is coupled to the flow cell for pressure sensor 205. Theflow cell for pressure sensor 205 measures the pressure generated by thepump and pump tubing 203, respectively. Also, the flow cell for pressuresensor 205 is connected to the air trap 207, which allows for removal ofair in buffers and sample. The air trap 207 is filled (air is evacuated)by pressing an AIR VENT button. The air vent tubing 209 is connected tothe air trap 207, where the air vent tubing 209 is used for ventilationof air to/from the air trap 207. The column inlet connection 211 is alsoconnected to the air trap 207, where the connector to column inlettubing is a sanitary TC connector. The column outlet connection 213 isconnected to the column inlet connection 211, where the column outletconnection 213 acts as the connector to column outlet tubing. Allexternal connections of the flow path at inlets and outlets may equallybe equipped with aseptic connectors that provide aseptic connections ina non-aseptic environment, thereby maintaining flow path sterility.

Next to the column outlet connection 213 is the flow cell for pressuresensor 215; this flow cell for pressure sensor 215 measures the pressurebetween the pump and the column. A pH electrode 217 can be mounted onthe flow cell for pressure sensor 215. This pH electrode 217 measuresthe pH of the liquid. The flow meter cell 219 is connected to the flowcell for pressure sensor 215, where the flow meter cell 219 measuresliquid velocity by using ultrasound. The temperature cell 221 isconnected to the flow meter cell 219, where the temperature cellcontains a surface prepared for measuring temperature by means ofemitted infrared light detection. Next to the temperature cell 221 isthe conductivity sensor 223 that measures the conductivity of theliquid. The ultraviolet (UV) flow cell 225 is located next to theconductivity sensor 223, where the UV flow cell is used as a UVdetector. The flow cell for pressure sensor 229 is connected to the UVflow cell 225, where the flow cell for pressure sensor 229 is a flowcell for safety pressure sensor that measures pressure in the liquidafter the sensors. The outlet manifold 227 is connected to the flow cellfor pressure sensor 229, where the outlet manifold has 6 outletscorresponding to TC connectors.

FIG. 3 shows a schematic of the ÄKTAREADY™ flow path as liquid flowsthrough a typical ÄKTAREADY™ system. Inlet valves of the inlet manifold201 (FIG. 2) opens the appropriate inlet for the sample or buffer. Thesample or buffer may be referred to as a liquid. The system pumpconnected to the pump tubing 203 delivers the liquid to the column 105(FIG. 1) via the pressure sensor 205, and, if preferred, via the airtrap 207 where air in the liquid is removed. There are two sets ofvalves for the inlet manifold 201 and the outlet manifold 229 and twoadditional sets of valves between the pump tubing 203 and the column105: the air trap 207 manifold, which allows for bypassing the air trap207, and the column manifold, also allows for bypassing the column 105.

Downstream the column 105, the liquid passes through a second pressurecell 215 (FIG. 2), which has an integrated flow cell for the pHelectrode 217. The liquid then continues through the flow meter cell 219with integrated temperature measurement 221, the conductivity cell 223,and the UV flow cell 225. The last sensor in the path is a thirdpressure flow cell for pressure sensor 227. Downstream the flow cell forpressure sensor 227, the liquid continues via the tubing of the outletmanifold 229, where valves divert the liquid to either waste or fractioncollection. At the outlet manifold 229, the ÄKTAREADY™ system worksunder a pressure of max 0.95 bar. Between pump tubing 203 and column 105the pressure is max 5 bar, and between column 105 and outlet manifold229 the pressure is max 3 bar. The different pressure zones aremonitored by flow cell for pressure sensors 205, 215 and 227.

FIG. 4 is a flow-chart of a computer automated installation procedure ofa disposable flow path of the ÄKTAREADY™ system of FIG. 1 in accordancewith invention. The UNICORN™ software, which is the standard softwarestored on the processor, memory or database of the ÄKTAREADY™ systemthat controls the ÄKTAREADY™ system, is the software that will controlthe operation of the disposable flow path procedure. Disposable meansthat the flow path will only be used for a single use or single batch,where there will be no cleaning or re-utilization of the flow path afterit is used once. Specifically, the wizard was created to guarantee thatflow paths and Ready to Process columns are correctly installed everytime and to be applicable in a Good Manufacture Procedure (GMP)environment. In order to guarantee that a flow path or a column iscorrectly installed, the method wizard dialog is built up with detailedinstallation steps that are followed by a user.

At block 401, the computer provides a step by step guidance for a properinstallation of all flow path components, for example a pump tubing 203(FIG. 2), flow cell for pressure sensor 205, flow cell for pressuresensor 215 and flow cell for pressure sensor 227 on the flow path 103.Flow path 103 or flow-kit may also be referred to as a non-disposableinstrument or a re-usable instrument on the ÄKTA™ Explorer 100. The pumptubing 203, flow cell for pressure sensor 205, flow cell for pressuresensor 215 and the flow cell for pressure sensor 227 are sterilized bygamma irradiation utilizing the standard means of gamma sterilizingcomponents. Next, at block 403 there is a qualification test of thetubing and aforementioned sensor to be on the flow path based on thestandard.

The test is performed in a predefined order and at some steps if thetest fail the test procedure immediately ends and the user is instructedto go through the troubleshooting guide with probable causes described.First, the flow meter cell 219 is tested for proper connection to thetransducers. If this test fails the test procedure is immediately ended.After this step the complete system and used inlets during testprocedures are primed (filled with liquid). The next step is todetermine if the correct size of the flow kit is selected (High flow orLow flow) if the system detects that different size is installedcompared to selected in UNICORN™ the test ends, this is done bymeasuring the flow rate measured in flow meter cell 219 with a specificFlow rate percentage is set on the pump. Next step is testing the UVflow cell 225, 1M NaCl in 1% acetone in purified water is now pumpedthrough the flow kit, the signal from the UV flow cell 225 is measuredand tested if within the predetermined acceptance interval. The methodcontinues regardless if the test is a failed or passed. After this theconductivity cell 223 is tested with the same solution as in previousstep in a similar way but with different interval since now the measuredconductivity of the liquid is tested. The method continues regardless ifthe test is a failed or passed. After these steps the three pressuresensors are tested, starting with pressure sensor 205 followed bypressure sensor 215 and pressure sensor 227. Different back pressuresare generated by running the pump in different speeds. Each pressuresensor is tested individually and can result in a pass or fail, theprocedure will continue regardless of outcome of these steps. All passedand failed tests will be summarized together with raw data in a reportthat can be printed out automatically.

In another example, this qualification checks that the correct size oftubing is installed, that flow rate and system capacity specificationsare met with the flow path and that the flow meter provides expectedfunctionality. Further, sensor functionality is verified by pumpingsequentially a number of test solutions through the system that arecharacterized by different properties in regard to conductivity, lightabsorbance etc.

Next, at block 405 there is a determination if a plurality of componentsassociated with the tubing and the aforementioned sensors providemeasurement characteristics and performance in accordance with limitsfor specifications or acceptance criteria. This is done by automaticevaluation of the test data obtained in block 403 by the UNICORN™control system of the ÄKTAREADY™ system. In detail, experimental datarecorded in the different steps of the qualification test (block 403) iscompared with acceptance limits to qualify the respective flow pathcomponent. A report is generated that documents all qualification dataand serves the GMP documentation needs of the user.

If the tubing and sensor components do provide measurementcharacteristics and performance in accordance with limits forspecifications or acceptance criteria, then the process ends, where thereport is generated and the system is ready for use. In the case wherethe tubing and sensors do not provide measurement characteristics andperformance in accordance with limits for specifications or acceptancecriteria then the process would return to block 401 and a different flowpath may need to be installed. At this point, a report is automaticallygenerated by the ÄKTAREADY™ device that will provide a pass or failureof the functionality for the tested disposable flow path.

While the qualification and the potential failure of sensor componentsin block 405 primarily depends on the production quality assurance andspecifications of the sensor components itself, it is the automaticguidance of manual interaction by the user during flow path installationprovided by block 401 that is crucial for preventing potential errorsand risks that are associated with the use of a disposable flow pathcompared to using a non-disposable flow path and system.

This invention provides an automated installation procedure forassembling a disposable flow path. The user is able to provide a tubingand plurality of sensors to a flow path. Then the user is able toqualify the tubing and plurality of sensors and to automaticallydetermine if tubing or components associated with the tubing and if theplurality of sensors comply with characteristics and performanceaccording to limits for specifications or acceptance criteria. Thus, theuser is provided with a simple worry free method to install sterilizedtubing and a sterilized plurality of sensors onto a flow path that isquality tested.

Although the present invention has been described above in terms ofspecific embodiments, many modification and variations of this inventioncan be made as will be obvious to those skilled in the art, withoutdeparting from its spirit and scope as set forth in the followingclaims. In particular, the described invention may also be applied tothe removal of a used flow path from the system prior to disposal.Further, disposable tubing and components are preferably pre-sterilizedwhen used in biopharmaceutical applications.

What is claimed is:
 1. An automated installation procedure forassembling a disposable flow path comprising: providing tubing and aplurality of sensors to be installed onto a re-usable instrument;providing a step by step guidance for a proper installation; qualifyingthe tubing and the plurality of sensors in the disposable flow pathbased on a standard; and determining if the tubing and the plurality ofsensors comply with characteristics and performance according to limitsfor specifications or acceptance criteria by comparing experimental datarecorded in the qualifying step with acceptance limits to qualify therespective flow path component.
 2. The method of claim 1, wherein thedisposable flow path is pre-sterilized.
 3. The method of claim 1,wherein the flow path includes an inlet manifold, a pump tubing and amain part.
 4. The method of claim 1, further comprising generating areport if the tubing and the plurality of sensors has passed or failed afunctionality test.
 5. The method of claim 1, wherein the sterilizedplurality of sensors include components for measurement of at least oneof the types for measuring pressure, conductivity, UV absorbance andflow rate.
 6. The method of claim 1, wherein the tubing and plurality ofsensors are sterilized.
 7. The method of claim 6, wherein the sterilizedtubing and the sterilized plurality of sensors are gamma-sterilized. 8.The method of claim 1, wherein the tubing is a pump tubing of aperistaltic pump.
 9. A computer-implemented image processing method forassembling a disposable flow path comprising: providing tubing and aplurality of sensors to be installed onto a re-usable instrument;providing a step by step guidance for a proper installation; qualifyingthe tubing and the plurality of sensors in the flow path based on astandard; and determining if the tubing and the plurality of sensorscomply with characteristics and performance according to limits forspecifications or acceptance criteria by comparing experimental datarecorded in the qualifying step with acceptance limits to qualify therespective flow path component.